A study of inhibitors of d-glycero-β-d-manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei as a potential antibiotic target

d-Glycero-β-d-manno-heptose-1-phosphate adenylyltransferase from Burkholderia pseudomallei (BpHldC) is the fourth enzyme in the ADP‐l‐glycero‐β‐d‐manno‐heptose biosynthesis pathway producing a lipopolysaccharide core. Therefore, BpHldC is an anti-melioidosis target. Three ChemBridge compounds purchased from ChemBridge Corporation (San Diego, CA) were found to have an effective inhibitory activity on BpHldC. Interestingly, ChemBridge 7929959 was the most effective compound due to the presence of the terminal benzyl group. The enzyme kinetic study revealed that most of them show mixed type inhibitory modes against ATP and βG1P. The induced-fit docking indicated that the medium affinity of ChemBridge 7929959 is originated from its benzyl group occupying the substrate-binding pocket of BpHldC. The inhibitory role of terminal aromatic groups was proven with ChemBridge 7570508. Combined with the previous study, ChemBridge 7929959 is found to work as a dual inhibitor against both HldC and HddC. Therefore, three ChemBridge compounds can be developed as a potent anti-melioidosis agent with a novel inhibitory concept.     

Relation between warning stimuli and contingent negative variation in man

Seven right handed male students were submitted to standard and target paired auditory stimuli to determine the relationship between contingent negative variation (CNV) and the slow negative waves following non paired stimuli. The warning stimuli informed subjects whether or not the impending unconditional stimulus implied a motor response. Subjects were instructed to execute the motor task at less than one second after unconditional stimulus. They were informed that the standard warning stimulus would be followed by an additional stimulus which confirmed its detection. Recordings of standard warning stimulus condition showed a subsequent increase in CNV amplitude. This significant increase appeared to be related to an enhancement in the subject's expectation towards the additional stimulus. The lowered CNV voltage in target condition seemed to be linked to the instructions, which involved a motor preparation after the imperative stimuli occurrence. It is suggested that the CNV may represent not only a general anticipatory but also an orienting process related to the signal value of the warning stimulus.     

Greater epithelial ridge cells are the principal organoid-forming progenitors of the mouse cochlea

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